Endo et al., J. Antibiotics, XXIX, 1346 (1976) described a fermentation product, ML-236B, with potent antihypercholesterolemic activity which acts by inhibiting HMG-CoA reductase. This material, named compactin by Brown et al., J. Chem. Soc., Perkin I, 1165 (1976) was shown to have a desmethyl mevalonolactone partial structure and the stereochemistry was studied.
Shortly thereafter a chemically similar, natural product MK-803 (mevinolin), obtained by fermentation, was isolated and characterized, by Monaghan et al., U.S. Pat. No. 4,231,938. It has been shown to have the same desmethyl mevalonolactone partial structure and the absolute stereochemical configuration has been determined and described in EPO publication No. 0,022,478 of Merck & Co., Inc.
Totally synthetic analogs of these natural inhibitors have been prepared and described in Sankyo's U.S. Pat. No. 4,198,425 and Sankyo's U.S. Pat. No. 4,255,444 with no attempt being made to separate to stereo- and optical isomers. Subsequently, as described in Merck's EPO publication No. 0,024,348 and by Meyer, Ann. Chem., (1979), pages 484-491, similar totally synthetic analogs were separated into their stereoisomers and optical enantiomers. Furthermore, it was shown in EPO publication No. 0,024,348 that essentially all of the HMG-CoA reductase activity resides in the 4(R)-trans species as in the case with the naturally occurring compounds compactin and mevinolin.
In most of the prior art processes for preparing the totally synthetic compounds, the lactone moiety of each compound had to be elaborated by a lengthy series of synthetic operations followed by very tedious and expensive chromatographic separation of the cis, trans racemates, or enantiomers, following which, the inactive cis-isomer would be discarded.
A process for the preparation of the lactone ring system in the correct optically active form was recently reported by Majewski et al., Tetrahedron Lett., 1984, 2101-2104 utilizing a (3S,5S) iodoketal of the following formula: ##STR1##
Additionally, a process for the preparation of HMG-CoA reductase inhibitors using alkyl 5(R),6-epoxy-3(R)-(alkoxy)hexanoate as a chiral synthon for the stereospecific introduction of 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety is disclosed and claimed in U.S. patent application Ser. No. 673,231, filed Nov. 19, 1984.
Further, filed contemporaneously herewith is U.S. patent application Ser. No. 696,965 wherein a process for the preparation of HMG-CoA reductase inhibitors using alkyl 4-halo-3(S)-hydroxybutanoate as a chiral synthon for the 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety is described and claimed.